Congestive heart failure is a diseased state in which there is circulatory congestion, and abnormal accumulation of fluid in the organs and blood of a subject, which is secondary to heart failure. The diseased condition occurs when the volume of blood delivered into the systemic circulation is chronically reduced and when one or both ventricles of the heart fail to expel the normal fraction of the blood delivered to it. In these instances, a complex sequence of biochemical and anatomical adjustments occurs that ultimately results in an abnormal accumulation of fluid in the heart and blood vessels. Initially, there may be heart failure without congestion, but if the process continues in normal development, congestive heart failure will ensue rapidly or gradually. The hallmark of congestive heart failure is a decreased cardiac output associated with an abnormally elevated peripheral vascular resistance.
Although the term "congestive heart failure" usually denotes failure of both ventricles, most typically it is an initial dysfunction of the left side that results in the subsequent failure of the right side. The accompanying venous congestion usually involves both the pulmonary and systemic capillary beds, but congestion may be limited to either one alone.
Individuals suffering from this condition frequently exhibit breathlessness which worsens with increasing physical activity (which demands an increased cardiac output). This symptom results from elevated pulmonary venous and capillary pressures that force fluid into the interstitium of the lung thereby increasing the work of breathing. Often the fluid transudes into the alveolar spaces of the lung causing pulmonary oedema; night time episodes of pulmonary oedema are common symptoms of pulmonary venous congestion. Right-sided heart failure elevates systemic venous pressure; its principal symptoms are peripheral oedema and abdominal discomfort from hepatic enlargement.
Physical examination of afflicted persons demonstrates a variety of additional signs and symptoms. Often, a lowered cardiac output causes the person to appear pale and clammy. The presence of alveolar fluid may be detected as rales on lung examination. Systemic venous hypertension is demonstrated by elevated jugular venous pressure, liver engorgement and peripheral oedema. Frequently the heart is also enlarged. A third heart sound may often be heard which is an indication of reduced left ventricular compliance; a fourth heart sound may also be present. A chest radiograph usually confirms the existence of cardiac enlargement and shows venous redistribution or overt pulmonary oedema.
The treatment of congestive heart failure is aimed at correcting the basic physiological derangements. Oxygen may be given to improve pulmonary gas exchange; diuretics may be given to reduce venous hypertension and cardiac filling; often, a drug which improves myocardial contractility is given. Recently, drugs that reduce the elevated systemic vascular resistance or "afterload" have become increasingly popular, both for acute and chronic treatment of this condition. When the acute symptoms have been abated, a search for the etiology of heart failure is then undertaken. Although the prognosis depends on the underlying cause, less than fifty percent of those individuals afflicted with congestive heart failure are alive five years after onset of the clinical condition.
One of the primary difficulties in treating human patients with congestive heart failure is that the causes or sources of the elevated systemic vascular resistance and oedema are varied and are mostly due to changes and adjustments in three different vasopressor systems of the body, each of which interacts directly with the others. These are: the sympathetic nervous system stimulations; the renin-angiotensin system; and neurohypophyseal secretion of vasopressin (antidiuretic hormone or arginine vasopressin).
The sympathetic nervous system is a part of the autonomic nervous system and represents a series of peripheral spinal nerves which innervate most visceral organs, the sweat glands and blood vessels of the body, and the skeletal muscles. Stimulation of particular sympathic nerves effects dilation of the pupils; vasoconstriction of the blood vessels of the skin and viscera; vasodilation of the blood vessels of skeletal muscles, cardiac muscle and the skin of the face; and contraction of the splenic capsule which directly results in the expulsion of red blood cells into the systemic circulation. Such stimulation also increases sweat secretion, increases the heart rate, and increases the release of renin from the kidney.
The activity of the renin-angiotension system biochemically involves a class of polypeptide hormones derived from an angiotensinogen precursor substrate by action of the proteolytic enzyme renin, which is itself secreted by the juxtaglomerular cells in the kidney. The enzyme renin is secreted in response to low blood volume, a decreased of blood pressure, or an increased stimulation of the renal sympathetic nerves. This enzyme acts upon angiotensinogen to release the polypeptide angiotensin I, which in turn is converted into angiotensin II. Angiotensin II which is an octapeptide hormone and one of the most powerful vasoconstrictor known. Its main actions are constriction of arterioles to increase blood pressure and stimulation of the adrenal zona glomerulosa to secrete aldosterone, a hormone that acts on the kidney to cause retention of salt and fluid. Angiotensin II also performs a variety of other roles including: exerting a negative feedback effect on the juxtaglomerular cells to decrease the rate of renin secretion; acting upon receptor areas in the brain that in turn stimulate an increase in water uptake and vasopressin secretion; and modulating sympathetic nerve functions via its action upon peripheral neurons.
Vasopressin, also known as antidiuretic hormone and arginine vasopressin, is a cyclic polypeptide that is formed in the hypothalamus and is stored in the posterior lobe of the pituitary gland. Vasopressin is released into the body as necessary to stimulate smooth muscle in the walls of small blood vessels to contract and to raise the overall blood pressure of the body. Vasopressin also conserves body water by promoting reabsorption of water in the distal convoluted tubules of the kidney thus resulting in more concentrated urine.
In persons afflicted with congestive heart failure, the elevated vascular resistance has been empirically demonstrated to result partly from sympathetic nervous system stimulation and partly from increased activity of the renin-angiotensin system [Zelis and Flaim, Prog. Cardiovasc. Dis. 24: 437-459 (1982)]. Some investigators have also speculated that the secretion of vasopressin may also be directly involved in the pathological state since its concentration is often, but not always, increased in those patients afflicted with congestive heart failure [Yamane, Y., Jpn. Circ. J. 32: 745-759 (1968); Riegger et al., Am. J. Med. 72: 49-52 (1982); Szatalowicz et al., N. Engl. J. Med. 305: 263-266 (1981); Goldsmith et al., J. Am. Coll. Cardiol. 1: 1385-1390 (1983); Preibisz et al. Hypertension 5: 1129-1138 (1983)]. Similarly, elevated plasma levels of vasopressin have been reported in animal studies with subjects demonstrating low output heart failure [Anderson et al., J. Clin. Invest. 54: 1473-1479 (1974); Riegger and Liebau, Clin. Sci. 62: 465-469 (1982); Thrasher et al., Am. J. Physiol. 244: R850-856 (1983)].
Experimentally, it has been demonstrated that vasoconstriction does not occur when physiological doses of arginine-vasopressin (hereinafter "AVP") are applied to the femoral artery [Monos et al., Am. J. Physiol. 234: H167-172 (1978)]. Animal studies have shown that AVP, when endogenously oversecreted during dehydration, hemorrhage or hyperosmolality, has a vasopressor effect [Montani et al. Circ. Res. 47: 346-355 (1980); Aisenbrey et al., J. Clin. Invest. 67: 961-968 (1981)] and that such levels of vasopressin have a more pronounced pressor action in animals subjected to baroreceptor denervation, sympathectomy and/or nephrectomy [Cowley et al., Circ. Res. 46: 58-67 (1980); Gavras et al., Hypertension 4: 400-405 (1982)]. In addition, the AVP concentration present in patients with congestive heart failure enhances the renal tubular reabsorption of water [Bercu et al., Circulation 2: 409-413 (1950); Leaf and Mamby, J. Clin. Invest. 31: 60-71 (1952); White et al., J. Clin. Invest. 32: 931-939 (1953)].
Relatively few studies have actually examined the vasopressor effect of endogenous AVP in human subjects. Recently, using an antagonist of AVP at the vascular V.sub.1 receptors, it was demonstrated that when administered to normally hydrated healthy human subjects, this AVP antagonist did not alter blood pressure [Manning et al., J. Med. Chem. 25: 45-50 (1982); Bussin et al., Am. J. Physiol. 246: H143-147 (1984)]; subsequent investigations revealed, however, that this AVP antagonist did in fact decrease the blood pressure in sodium-loaded patients with end-stage renal disease in whom plasma AVP concentration was found to be increased above normal values [Gavras et al., Hypertension (Suppl. I) 6: 156-160 (1984)].
It is readily recognized, therefore, that the relationship of vasopressin to the renin-angiotensin system and the sympathetic nervous system is a complex and poorly understood phenomenon. Angiotension II has been reported to usually increase vasopressin levels; similarly, there have been reports that norepinephrine decreases the effectiveness of vasopressin. Insofar as is presently known, however, there is no information whether concentrations of vasopressin above normal levels are able to cause vasoconstriction in human patients with congestive heart failure. Furthermore, there is no knowledge and no factual basis upon which to predict whether a selective antagonist could act as a therapeutic agent to provide a decrease in systemic vascular resistance in persons afflicted with congestive heart failure.